NK cell regulation of immune responses to dengue

 描述(申请人提供)：自然杀伤(NK)细胞是先天免疫反应的主要效应细胞，在几种疾病模型中在控制病毒复制方面发挥关键作用。在小鼠和人类中，NK细胞的耗尽或缺乏都会导致更严重的病毒疾病和死亡。杀伤免疫球蛋白样受体(KIRS)与人类白细胞抗原(HLAI)类配体相互作用，在自然杀伤(NK)细胞的调节和激活中发挥核心作用。因此，KIRS和它们的HLAI类配体之间的相互作用可以对NK细胞介导的病毒致病控制的有效性产生深远的影响，并已在许多慢性病毒感染中得到证实。关于NK细胞在调节登革热病毒感染中的作用，人们知之甚少。我们发现登革热非结构蛋白1(NS1)上的CD8T细胞表位与NK细胞上的抑制性受体KIR3DL1相互作用。在这一应用中，我们将使用抗原特异性四聚体和多肽来剖析与KIR3DL1的相互作用，并确定登革病毒如何调节这一重要的NK细胞亚群的功能。本申请中概述的研究将更好地了解KIR-MHC I类相互作用对NK细胞的重要性，并提供针对这一天然免疫反应臂以控制登革热病毒复制的理论基础。

 DESCRIPTION (provided by applicant): Natural Killer (NK) cells are primary effector cells of the innate immune response and play a critical role in the control of viral replication in several disease models. Depletions or deficiencies of NK cells lead to significantly more severe viral disease and death in both mice and humans. Killer immunoglobulin-like receptors (KIRs) interact with HLA class I ligands and play a central role in the regulation and activation of naturl killer (NK) cells. The interaction between KIRs and their HLA class I ligands can thus have a profound impact on the efficacy of NK cell-mediated control of viral pathogenesis and has been demonstrated for a number of chronic viral infections. Very little is known about the involvement of NK cells in regulating dengue virus infections. We have found that a CD8 T cell epitope on the non-structural protein 1 (NS1) of dengue interacts with a well characterized inhibitory receptor KIR3DL1 on NK cells. In this application, we will use the antigen-specific tetramers and peptides to dissect the interaction with KIR3DL1 and determine how dengue virus modulates the function of this important subset of NK cells. The studies outlined in this application will provide a better understanding of the importance of KIR-MHC class I interactions on NK cells and provide the rationale to target this innate arm of the immune response to control dengue virus replication.